PROJECT SUMMARY The Prokineticin Receptor 1 (ProKR1 or PKR1) is a vastly understudied GPCR that potently controls food intake energy expenditure and nociception. PKR1 stimulation causes a potent decrease in food intake and increase in energy expenditure. Deletion of PKR1 causes severe obesity and increased adiposity. As such it is an important novel target for the treatment of obesity. While this proposal will not be focusing on this aspect of PKR1 physiology, peripheral inhibition of PKR1 has been shown to decrease nociception and consequently, ligands for PKR1 represent a promising alternative to opioids for the treatment of pain. In this project we will focus on the role of PKR1 in the control of energy homeostasis. We propose to use innovative mouse models that we developed and validated to accurately map the distribution of PKR1 in the brain. The hypothalamus being the main center of regulation of energy homeostasis, we will identify the population of neurons within the hypothalamus that expresses PKR1. We have previously demonstrated that the Melanocortin Receptor Accessory Protein 2 (MRAP2) is an important regulator of PKR1. For this reason, we will also test in-vivo and ex-vivo, how MRAP2 regulates PKR1 trafficking and signaling in neurons and how the PKR1/MRAP2 complex is regulated by food intake and fasting. Results from those studies will largely improve our understanding of the roles of PKR1 and its regulation by energy homeostasis and MRAP2. They will also further demonstrate the value of PKR1 as a new target for the treatment of obesity.